This proposal outlines the continuation of studies of genetic causes of cell death in the substantia nigra, the cerebellum, and the testes in the weaver mutation. Weaver is a naturally occurring autosomal recessive mutation in mice that kills dopamine-containing neurons in the nigrostriatal tract, granule cells in cerebellum, and male germ cells. Within the dopamine-producing pathways, weaver discriminates between mesolimbic and nigrostriatal systems, leaving the mesolimbic pathway largely intact and the nigrostriatal system greatly damaged. The pattern of cell death seen in the weaver's midbrain is remarkably similar to that seen in Parkinson's disease and in humans and animals made parkinsonian through exposure to the neurotoxin MPTP. The goals for the study of weaver are to determine whether the dopamine- containing neurons in the substantia nigra and the male germ cells in the testes are primary or secondary targets of weaver. The mechanisms of cell death caused by weaver will be examined in its two targets in brain and in testes. We will determine whether cell death is caused in each of the vulnerable regions by apoptotic or other mechanisms. To explore the hypothesis that cell death caused by weaver is linked to failure of termination of developmental cell death, we will compare the relationship of the period of naturally occurring developmental cell death to the period of early cell death caused by the action of weaver. We will also investigate the possibility that cell death caused by weaver occurs subsequent to inappropriate cell cycling. Finally, we will attempt to block or delay cell death in the substantia nigra of weaver. These experiments aimed at prevention of cell death may also reveal cause. We will examine the effects of weaver in transgenic mice that overexpress the human gene Bcl-2, the product of which blocks most apoptosis, in the substantia nigra. In addition, we will conduct a series of experiments to determine the effectiveness of gene therapy for the weaver's substantia nigra. We plan to use retrovirus vectors to confer stable expression of genes for neurotrophic factors, beginning with BDNF, on fibroblasts implanted in the mesencephalon. The importance of the proposed work related to its potential for revealing causes of neurodegeneration.